What is Lormetazepam?

Introduction

Lormetazepam, sold under the brand name Noctamid among others, is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative and temazepam analogue. It possesses hypnotic, anxiolytic, anticonvulsant, sedative, and skeletal muscle relaxant properties.

It was patented in 1961 and came into medical use in 1980. Lormetazepam is not approved for sale in the United States or Canada. It is licensed in the UK as 0.5 and 1 mg tablets for short-term treatment (2-4 weeks) of moderately severe insomnia. It is licensed in the Netherlands as 1 and 2 mg tablets, under the brand names Loramet and Noctamid and as generic, available from several manufacturers. It is sold in Poland as Noctofer. A Dutch analysis stated that lormetazepam could be suitable to be included in drug prescribing formularies, although zolpidem, zopiclone, and temazepam appear better.

Medical Uses

Lormetazepam is considered a hypnotic benzodiazepine and is officially indicated for moderate to severe insomnia. Lormetazepam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or falling asleep. Hypnotics should only be used on a short-term basis or, in those with chronic insomnia, on an occasional basis.

Side Effects

Side effects of lormetazepam are similar to those of other hypnotic benzodiazepines and can for the most part be regarded as a class effect. In a sleep study, 1 mg lormetazepam increased total sleep time, reduced wakefulness, but did not alter REM sleep. However, at 2 mg doses, there were significant increases in stage 3 sleep and reductions in REM sleep. Rebound effects have been reported after chronic use including rebound REM. In one clinical trial with patients who had prior experience with older hypnotics temazepam and nitrazepam, most preferred lormetazepam due to less heavy sedation, amnesia, and residual effects. Some side effects, including drowsiness, amnesia, and respiratory depression, are increased when lormetazepam is combined with other drugs with similar effects, e.g. alcohol and nonbenzodiazepine drugs.

Although lormetazepam has been associated with adversely affecting immediate and delayed recall memory functions, studies have shown that lormetazepam’s amnesic properties may be lesser compared to other hypnotic benzodiazepines. For example, in a 1984 study comparing the amnesic effects of lormetazepam to temazepam and flurazepam showed that amnesia was smallest after lormetazepam and greatest after temazepam, which had produced greater amnesia than both lormetazepam and flurazepam by a significant margin.

Side effects of lormetazepam include:

  • Somnolence.
  • Paradoxical increase in aggression.
  • Lightheadedness.
  • Confusion.
  • Muscle weakness.
  • Ataxia (particularly in the elderly).
  • Anterograde amnesia.
  • Headache.
  • Vertigo.
  • Hypotension.
  • Salivation changes.
  • Gastro-intestinal disturbances.
  • Visual disturbances.
  • Dysarthria.
  • Tremor.
  • Changes in libido.
  • Incontinence.
  • Urinary retention.
  • Blood disorders and jaundice.
  • Skin reactions.
  • Dependence and withdrawal reactions.

Residual “hangover” effects after nighttime administration of lormetazepam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.

Benzodiazepines require special precaution if used during pregnancy, in children, in alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders. Lormetazepam may be unsuitable for the elderly due to residual effects on memory and body sway which may result in falls. Lormetazepam causes impaired driving skills, thus caution is required in individuals who drive or operate machinery.

Tolerance, Dependence, and Withdrawal

The risks of tolerance, dependence, and withdrawal are very low when the drug is used for 2-4 weeks only, and lormetazepam is generally a safe and effective drug when used for no longer than 2-4 weeks. Some sleep disturbance in the form of rebound insomnia can, however, occur even after short-term usage of 7 days. Those with a history of addiction may be at increased risk of problems of tolerance and dependence especially those with a past history of dependency on sedative hypnotic drugs.

Lormetazepam as with other benzodiazepines is generally only recommended for short-term use (2-4 weeks) due to tolerance and loss of efficacy. Tolerance to and loss of the sedative effects of benzodiazepine hypnotics can occur within 14 days of regular use. Some studies however suggest such treatments retain their effectiveness in the long term – such a lack of consistency in the findings of many studies could be due to the variation of responses to benzodiazepine treatment.

Dependence is the medical term for addiction. Dependence can either be psychological and/or physical. Psychological dependence can manifest itself as a reliance on a drug to cope with everyday life or in the form of craving. Physical dependence occurs due to physiological adaptations occurring as the body attempts to overcome the drugs effects which is known as tolerance and the continuing need to take the drug to avoid or suppress withdrawal symptoms which can sometimes resemble the original condition being treated. When the dose or the drug is discontinued withdrawal symptoms typically occur. Lormetazepam as with all other benzodiazepines produces both physical and psychological dependence but the main problem of concern is physical dependence which appears in the form of the benzodiazepine withdrawal syndrome after the dosage is reduced or the drug is stopped completely. The dependence induced by lormetazepam is related to changes in the sensitivity of the GABA-BZD receptor complex.

Withdrawal symptoms which can occur from stopping benzodiazepines such as lormetazepam can include:

  • Rebound insomnia and nightmares.
  • Anxiety, panic attacks, and agoraphobia.
  • Clinical depression.
  • Malaise.
  • Lack of concentration.
  • Abdominal discomfort.
  • Depersonalisation and feelings of unreality.
  • Emotional lability.
  • Cognitive impairment.
  • Tinnitus.
  • Paraesthesiae, tingling, numbness, and pain.
  • Muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, blepharospasm.
  • Excitability, jumpiness, and restlessness.
  • Stiffness.
  • Sweats.

Abrupt or over rapid withdrawal from high doses can provoke:

Withdrawal symptoms typically subside after 4-8 weeks but in approximately 10-15% of individuals symptoms can persist for many months and in rare cases years. Some “Withdrawal Symptoms” can emerge despite a constant dosage with the body needing extra dosage in order to feel normal. This is sometimes associated with dosage escalation.

Lormetazepam has a short to intermediate half-life of approximately 10-12 hours. Shorter acting benzodiazepine compounds are generally associated with a more intense and immediate withdrawal reaction compared to longer acting benzodiazepines. For this reason it is generally recommended to cross from lormetazepam to an equivalent dose of diazepam to gradually taper the dosage.

Pharmacology

The bioavailability of lormetazepam was found to be 80%.

Lormetazepam and other benzodiazepine drugs act as positive modulators at the GABAA benzodiazepine receptor complex. Lormetazepam binds to the benzodiazepine receptor which in turn enhances the effect of the GABAA receptor producing its therapeutic effects as well as adverse effects. When lormetazepam binds to the benzodiazepine receptor sites in sufficient quantities it produces sedation which is used clinically as a therapeutic treatment for insomnia. Lormetazepam alters the brain electrical activity which has been studied via EEG readings. Lormetazepam appears to be more selective in the type of benzodiazepine receptor it binds to showing a higher affinity for the omega 1 receptor which is responsible for sedation. Changes in EEG can therefore be used to measure the sedative sleep promoting properties of lormetazepam.

Trade Names

Trade names include Aldosomnil, Dilamet, Ergocalm, Loramet, Loretam, Metatop, Minias, Noctamid, Noctamide, Noctofer, Nocton, Pronoctan, Sedaben, and Stilaze.

Stereochemistry

Lormetazepam has a stereocenter and two enantiomers. Medications are racemates.

Book: Doctoring the Mind: Why Psychiatric Treatments Fail

Book Title:

Doctoring the Mind: Why Psychiatric Treatments Fail.

Author(s): Richard P. Bentall.

Year: 2010.

Edition: First (1st).

Publisher: Penguin.

Type(s): Hardcover, Paperback and Kindle.

Synopsis:

Why is the Western world’s treatment of mental illness so flawed? Who really benefits from psychiatry? And why would a patient in Nigeria have a much greater chance of recovery than one in the UK?

In Doctoring the Mind, leading clinical psychologist Richard Bentall reveals the shocking truths behind the system of mental health care in the West. With a heavy dependence on pills and the profit they bring, psychiatry has been relying on myths and misunderstandings of madness for too long, and builds on methods which can often hinder rather than help the patient.

Bentall argues passionately for a new future of mental health, one that considers the patient as an individual and redefines our understanding and treatment of madness for the twenty-first century.

What is Tacrine?

Introduction

Tacrine is a centrally acting acetylcholinesterase inhibitor and indirect cholinergic agonist (parasympathomimetic).

It was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer’s disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the University of Sydney in 1949. It also acts as a histamine N-methyltransferase inhibitor.

Clinical Use

Tacrine was the prototypical cholinesterase inhibitor for the treatment of Alzheimer’s disease. William K. Summers received a patent for this use in 1989. Studies found that it may have a small beneficial effect on cognition and other clinical measures, though study data was limited and the clinical relevance of these findings was unclear.

Tacrine has been discontinued in the US in 2013, due to concerns over safety.

Tacrine was also described as an analeptic agent used to promote mental alertness.

Adverse Effects

  • Very common (>10% incidence) adverse effects include:
    • Increased LFTs.
    • Nausea.
    • Vomiting.
    • Diarrhoea.
    • Headache.
    • Dizziness.
  • Common (1-10% incidence) adverse effects include:
    • Indigestion.
    • Belching.
    • Abdominal pain.
    • Myalgia – muscle pain.
    • Confusion.
    • Ataxia – decreased control over bodily movements.
    • Insomnia.
    • Rhinitis.
    • Rash.
    • Fatigue.
    • Weight loss.
    • Constipation.
    • Somnolence.
    • Tremor.
    • Anxiety.
    • Urinary incontinence.
    • Hallucinations.
    • Agitation.
    • Conjunctivitis (a link to tacrine treatment has not been conclusively proven).
    • Diaphoresis – sweating.
  • Uncommon/rare (<1% incidence) adverse effects include:
    • Hepatotoxicity (that is toxic effects on the liver).
    • Ototoxicity (hearing/ear damage; a link to tacrine treatment has not been conclusively proven).
    • Seizures.
    • Agranulocytosis (a link between treatment and this adverse effect has not been proven) – a potentially fatal drop in white blood cells, the body’s immune/defensive cells.
    • Taste changes.
  • Unknown incidence adverse effects include:
    • Urinary tract infection.
    • Delirium.
    • Other optic effects such as glaucoma, cataracts, etc. (also not conclusively linked to tacrine treatment).
    • Depression.
    • Suicidal ideation and behaviour.
    • Hypotension.
    • Bradycardia.

Overdose

As stated above, overdosage of tacrine may give rise to severe side effects such as nausea, vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Atropine is a popular treatment for overdose.

Pharmacokinetics

Major form of metabolism is in the liver via hydroxylation of benzylic carbon by CYP1A2. This forms the major metabolite 1-hydroxy-tacrine (velnacrine) which is still active.

What is a Serotonergic Drug?

Introduction

Serotonergic means “pertaining to or affecting serotonin”.

Background

Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron produces serotonin. A substance is serotonergic if it produces its effects via interactions with the serotonin system, such as by stimulating or blocking neurotransmission.

A serotonergic or serotoninergic agent is any chemical that modifies the effects of serotonin in the body. Some different types of serotonergics drugs include the following:

  • Serotonin receptor agonists and antagonists;
  • Serotonin reuptake inhibitors; and
  • Serotonin releasing agents.

What is Triazolam?

Introduction

Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives.

It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties, triazolam’s amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced, as well. Due to its short half-life, triazolam is not effective for patients who experience frequent awakenings or early wakening.

Triazolam was initially patented in 1970 and went on sale in the United States in 1982. In 2017, it was the 280th most commonly prescribed medication in the United States, with more than one million prescriptions.

Medical Uses

Triazolam is usually used for short-term treatment of acute insomnia and circadian rhythm sleep disorders, including jet lag. It is an ideal benzodiazepine for this use because of its fast onset of action and short half-life. It puts a person to sleep for about 1.5 hours, allowing its user to avoid morning drowsiness. Triazolam is also sometimes used as an adjuvant in medical procedures requiring anaesthesia or to reduce anxiety during brief events, such as MRI scans and nonsurgical dental procedures. Triazolam is ineffective in maintaining sleep, however, due to its short half-life, with quazepam showing superiority.

Triazolam is frequently prescribed as a sleep aid for passengers travelling on short- to medium-duration flights. If this use is contemplated, the user avoiding the consumption of alcoholic beverages is especially important, as is trying a ground-based “rehearsal” of the medication to ensure that the side effects and potency of this medication are understood by the user prior to using it in a relatively more public environment (as disinhibition can be a common side effect, with potentially severe consequences). Triazolam causes anterograde amnesia, which is why so many dentists administer it to patients undergoing even minor dental procedures. This practice is known as sedation dentistry.

Side Effects

Adverse drug reactions associated with the use of triazolam include:

  • Relatively common (>1% of patients): somnolence, dizziness, feeling of lightness, coordination problems.
  • Less common (0.9% to 0.5% of patients): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances.
  • Rare (<0.5% of patients): constipation, taste alteration, diarrhoea, dry mouth, dermatitis/allergy, dreams/nightmares, insomnia, paraesthesia, tinnitus, dysesthesia, weakness, congestion.

Triazolam, although a short-acting benzodiazepine, may cause residual impairment into the next day, especially the next morning. A meta-analysis demonstrated that residual “hangover” effects after night-time administration of triazolam such as sleepiness, psychomotor impairment, and diminished cognitive functions may persist into the next day, which may impair the ability of users to drive safely and increase risks of falls and hip fractures. Confusion and amnesia have been reported.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance, Dependence, and Withdrawal

Refer to Benzodiazepine Withdrawal Syndrome.

A review of the literature found that long-term use of benzodiazepines, including triazolam, is associated with drug tolerance, drug dependence, rebound insomnia, and CNS-related adverse effects. Benzodiazepine hypnotics should be used at their lowest possible dose and for a short period of time. Nonpharmacological treatment options were found to yield sustained improvements in sleep quality. A worsening of insomnia (rebound insomnia) compared to baseline may occur after discontinuation of triazolam, even following short-term, single-dose therapy.

Other withdrawal symptoms can range from mild unpleasant feelings to a major withdrawal syndrome, including stomach cramps, vomiting, muscle cramps, sweating, tremor, and in rare cases, convulsions.

Contraindications

Benzodiazepines require special precautions if used in the elderly, during pregnancy, in children, in alcoholics, or in other drug-dependent individuals and individuals with comorbid psychiatric disorders. Triazolam belongs to the Pregnancy Category X of the FDA. It is known to have the potential to cause birth defects.

Elderly

Triazolam, similar to other benzodiazepines and nonbenzodiazepines, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments. Daytime withdrawal effects can occur.

An extensive review of the medical literature regarding the management of insomnia and the elderly found considerable evidence of the effectiveness and durability of nondrug treatments for insomnia in adults of all ages and that these interventions are underused. Compared with the benzodiazepines including triazolam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. Newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment, anterograde amnesia, daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. One study found no evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment for triazolam.

In addition, the effectiveness and safety of long-term use of these agents remain to be determined. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

Interactions

Ketoconazole and itraconazole have a profound effect on the pharmacokinetics of triazolam, leading to greatly enhanced effects. Anxiety, tremor, and depression have been documented in a case report following administration of nitrazepam and triazolam. Following administration of erythromycin, repetitive hallucinations and abnormal bodily sensations developed. The patient had, however, acute pneumonia, and kidney failure. Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in those with other physical complications. Caffeine reduces the effectiveness of triazolam. Other important interactions include cimetidine, diltiazem, fluconazole, grapefruit juice, isoniazid, itraconazole, nefazodone, rifampicin, ritonavir, and troleandomycin. Triazolam should not be administered to patients on Atripla.

Overdose

Refer to Benzodiazepine Overdose.

Symptoms of an overdose include:

  • Coma.
  • Hypoventilation (respiratory depression).
  • Somnolence (drowsiness).
  • Slurred speech.
  • Seizures.

Death can occur from triazolam overdose, but is more likely to occur in combination with other depressant drugs such as opioids, alcohol, or tricyclic antidepressants.

Pharmacology

The pharmacological effects of triazolam are similar to those of most other benzodiazepines. It does not generate active metabolites. Triazolam is a short-acting benzodiazepine, is lipophilic, and is metabolised hepatically via oxidative pathways. The main pharmacological effects of triazolam are the enhancement of the neurotransmitter GABA at the GABAA receptor. The half-life of triazolam is only 2 hours making it a very short acting benzodiazepine drug. It has anticonvulsant effects on brain function.

Society and Culture

Recreational Use

Refer to Benzodiazepine Drug Misuse.

Triazolam issued nonmedically: recreational use wherein the drug is taken to achieve a high or continued long-term dosing against medical advice.

Legal Status

Triazolam is a Schedule IV drug under the Convention on Psychotropic Substances and the US Controlled Substances Act.

Brandnames

The drug is marketed in English-speaking countries under the brand names Apo-Triazo, Halcion, Hypam, and Trilam. Other (designer) names include 2′-chloroxanax, chloroxanax, triclazolam, and chlorotriazolam.

What is Zimelidine?

Introduction

Zimelidine (INN, BAN) (brand names Zimeldine, Normud, Zelmid) was one of the first selective serotonin reuptake inhibitor (SSRI) antidepressants to be marketed.

It is a pyridylallylamine, and is structurally different from other antidepressants.

Zimelidine was developed in the late 1970s and early 1980s by Arvid Carlsson, who was then working for the Swedish company Astra AB. It was discovered following a search for drugs with structures similar to brompheniramine (it is a derivative of brompheniramine), an antihistamine with antidepressant activity. Zimelidine was first sold in 1982.

While zimelidine had a very favourable safety profile, within a year and a half of its introduction, rare case reports of Guillain–Barré syndrome emerged that appeared to be caused by the drug, prompting its manufacturer to withdraw it from the market. After its withdrawal, it was succeeded by fluvoxamine and fluoxetine (derived from the antihistamine diphenhydramine) in that order, and the other SSRIs.

Mechanism of Action

The mode of action is a strong reuptake inhibition of serotonin from the synaptic cleft. Postsynaptic receptors are not acted upon.

Other Uses

Zimelidine was reported by Montplaisir and Godbout to be very effective for cataplexy in 1986, back when this was usually controlled by tricyclic antidepressants, which often had anticholinergic effects. Zimelidine was able to improve cataplexy without causing daytime sleepiness.

Side Effects

Most often reported were:

  • Dry mouth, dryness of pharyngeal and nasal membranes.
  • Increased sweating (hyperhidrosis).
  • Vertigo.
  • Nausea.

Interactions

MAO inhibitors – severe or life-threatening reactions possible.

What is Escitalopram?

Introduction

Escitalopram, sold under the brand names Cipralex and Lexapro, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder (MDD) or generalised anxiety disorder (GAD). It is taken by mouth.

Common side effects include trouble sleeping, nausea, sexual problems, and feeling tired. More serious side effects may include suicide in people under the age of 25. It is unclear if use during pregnancy or breastfeeding is safe. Escitalopram is the (S)-stereoisomer (left-handed version) of citalopram (which exists as a racemate), hence the name escitalopram. In other words, escitalopram is a chiral switch of citalopram.

Escitalopram was approved for medical use in the United States in 2002. Escitalopram is sometimes replaced by twice the dose of citalopram. In 2018, it was the 22nd most commonly prescribed medication in the United States with more than 25 million prescriptions.

Brief History

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.

The FDA issued the approval of escitalopram for major depression in August 2002 and for GAD in December 2003. On 23 May 2006, the FDA approved a generic version of escitalopram by Teva. On 14 July of that year, however, the US District Court of Delaware decided in favour of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.

In 2006, Forest Laboratories was granted an 828-day (2 years and 3 months) extension on its US patent for escitalopram. This pushed the patent expiration date from 07 December 2009, to 14 September 2011. Together with the 6-month paediatric exclusivity, the final expiration date was 14 March 2012.

Medical Uses

Escitalopram has FDA approval for the treatment of major depressive disorder in adolescents and adults, and generalized anxiety disorder in adults. In European countries and the United Kingdom, it is approved for depression (MDD) and anxiety disorders, these include: GAD, social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder with or without agoraphobia. In Australia it is approved for major depressive disorder.

Depression

Escitalopram was approved by regulatory authorities for the treatment of major depressive disorder on the basis of four placebo-controlled, double-blind trials, three of which demonstrated a statistical superiority over placebo.

Controversy existed regarding the effectiveness of escitalopram compared with its predecessor, citalopram. The importance of this issue followed from the greater cost of escitalopram relative to the generic mixture of isomers of citalopram, prior to the expiration of the escitalopram patent in 2012, which led to charges of evergreening. Accordingly, this issue has been examined in at least 10 different systematic reviews and meta analyses. As of 2012, reviews had concluded (with caveats in some cases) that escitalopram is modestly superior to citalopram in efficacy and tolerability.

A 2011 review concluded that second-generation antidepressants appear equally effective, although they may differ in onset and side effects. Treatment guidelines issued by the National Institute of Health and Clinical Excellence and by the American Psychiatric Association generally reflect this viewpoint.

In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed escitalopram to be one of the most effective.

Anxiety Disorder

Escitalopram appears to be effective in treating general anxiety disorder, with relapse on escitalopram at 20% rather than placebo at 50%.

Escitalopram appears effective in treating social anxiety disorder.

Other

Escitalopram is effective in reducing the symptoms of premenstrual syndrome, whether taken continuously or in the luteal phase only. There are no good data available for escitalopram as treatment for seasonal affective disorder as of 2021.

Side Effects

Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido, delayed ejaculation, and anorgasmia.

There is also evidence that SSRIs may cause an increase in suicidal ideation. An analysis conducted by the FDA found a statistically insignificant 1.5 to 2.4-fold (depending on the statistical technique used) increase of suicidality among the adults treated with escitalopram for psychiatric indications. The authors of a related study note the general problem with statistical approaches: due to the rarity of suicidal events in clinical trials, it is hard to draw firm conclusions with a sample smaller than two million patients.

Citalopram and escitalopram are associated with dose-dependent QT interval prolongation and should not be used in those with congenital long QT syndrome or known pre-existing QT interval prolongation, or in combination with other medicines that prolong the QT interval. ECG measurements should be considered for patients with cardiac disease, and electrolyte disturbances should be corrected before starting treatment. In December 2011, the UK implemented new restrictions on the maximum daily doses at 20 mg for adults and 10 mg for those older than 65 years or with liver impairment. There are concerns of higher rates of QT prolongation and torsades de pointes compared with other SSRIs. The US Food and Drug Administration (FDA) and Health Canada did not similarly order restrictions on escitalopram dosage, only on its predecessor citalopram.

Very Common Effects

Very common effects (>10% incidence) include:

  • Headache (24%).
  • Nausea (18%).
  • Ejaculation disorder (9-14%).
  • Somnolence (4-13%).
  • Insomnia (7-12%).

Common Effects

Common effects (1-10% incidence) include:

  • Insomnia.
  • Somnolence (sleepiness).
  • Dizziness.
  • Paraesthesia.
  • Tremor.
  • Decreased or increased appetite.
  • Anxiety.
  • Restlessness.
  • Abnormal dreams.
  • Libido decreased.
  • Anorgasmia.
  • Sinusitis (nasal congestion).
  • Yawning.
  • Diarrhoea.
  • Constipation.
  • Vomiting.
  • Dry mouth.
  • Excessive sweating.
  • Arthralgia (joint pain).
  • Myalgia (muscular aches and pains).
  • Fatigue.
  • Pyrexia (fever).
  • Impotence (erectile dysfunction).

Psychomotor Effects

The most common effect is fatigue or somnolence, particularly in older adults, although patients with pre-existing daytime sleepiness and fatigue may experience paradoxical improvement of these symptoms. Escitalopram has not been shown to affect serial reaction time, logical reasoning, serial subtraction, multitask, or MacWorth clock task performance.

Discontinuation Symptoms

Refer to Antidepressant Discontinuation Syndrome.

Escitalopram discontinuation, particularly abruptly, may cause certain withdrawal symptoms such as anhedonia (83%), “electric shock” sensations, colloquially called “brain shivers” or “brain zaps” by sufferers. Frequent symptoms in one study were dizziness (44%), muscle tension (44%), chills (44%), confusion or trouble concentrating (40%), amnesia (28%), and crying (28%). Very slow tapering was recommended. There have been spontaneous reports of discontinuation of Lexapro and other SSRIs and SNRIs, especially when abrupt, leading to dysphoric mood, irritability, agitation, anxiety, headache, lethargy, emotional lability, insomnia, and hypomania. Other symptoms such as panic attacks, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), mania, worsening of depression, and suicidal ideation can emerge when the dose is adjusted down.

Sexual Dysfunction

Some people experience persistent sexual side effects after they stop taking SSRIs. This is known as post-SSRI sexual dysfunction (PSSD). Common symptoms include genital anaesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. Rates are unknown, and there is no established treatment.

Pregnancy

Antidepressant exposure (including escitalopram) is associated with shorter duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). Antidepressant exposure is not associated with an increased risk of spontaneous abortion. There is a tentative association of SSRI use during pregnancy with heart problems in the baby. The advantages of their use during pregnancy may thus outweigh the possible negative effects on the baby.

Overdose

Excessive doses of escitalopram usually cause relatively minor untoward effects, such as agitation and tachycardia. However, dyskinesia, hypertonia, and clonus may occur in some cases. Therapeutic blood levels of escitalopram are usually in the range of 20-80 μg/L but may reach 80-200 μg/L in the elderly, patients with hepatic dysfunction, those who are poor CYP2C19 metabolisers or following acute overdose. Monitoring of the drug in plasma or serum is generally accomplished using chromatographic methods. Chiral techniques are available to distinguish escitalopram from its racemate, citalopram.

Pharmacology

Mechanism of Action

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently available, escitalopram has the highest selectivity for the serotonin transporter (SERT) compared to the norepinephrine transporter (NET), making the side-effect profile relatively mild in comparison to less-selective SSRIs.

Escitalopram is a substrate of P-glycoprotein and hence P-glycoprotein inhibitors such as verapamil and quinidine may improve its blood brain barrier penetrability. In a preclinical study in rats combining escitalopram with a P-glycoprotein inhibitor, its antidepressant-like effects were enhanced.

Interactions

Escitalopram, similarly to other SSRIs, inhibits CYP2D6 and hence may increase plasma levels of a number of CYP2D6 substrates such as aripiprazole, risperidone, tramadol, codeine, etc. As escitalopram is only a weak inhibitor of CYP2D6, analgesia from tramadol may not be affected. Escitalopram should be taken with caution when using St. John’s wort. Exposure to escitalopram is increased moderately, by about 50%, when it is taken with omeprazole. The authors of this study suggested that this increase is unlikely to be of clinical concern. Caution should be used when taking cough medicine containing dextromethorphan (DXM) as serotonin syndrome has been reported.

Bupropion has been found to significantly increase citalopram plasma concentration and systemic exposure; as of April 2018 the interaction with escitalopram had not been studied, but some monographs warned of the potential interaction.

Escitalopram can also prolong the QT interval and hence it is not recommended in patients that are concurrently on other medications that also have the ability to prolong the QT interval. These drugs include antiarrhythmics, antipsychotics, tricyclic antidepressants, some antihistamines (astemizole, mizolastine) and some antiretrovirals (ritonavir, saquinavir, lopinavir). As an SSRI, escitalopram should generally not be given concurrently with MAOIs.

Chemistry

Escitalopram is the (S)-stereoisomer (left-handed version) of the racemate citalopram, which is responsible for its name: escitalopram. The (R)-stereoisomer (R-citalopram, the right-handed version) is not thought to have useful effects for treating depression.

Society and Culture

Allegations of Illegal Marketing

In 2004, separate civil suits alleging illegal marketing of citalopram and escitalopram for use by children and teenagers by Forest were initiated by two whistleblowers: a physician named Joseph Piacentile and a Forest salesman named Christopher Gobble. In February 2009, the suits were joined. Eleven states and the District of Columbia filed notices of intent to intervene as plaintiffs in the action.

The suits alleged that Forest illegally engaged in off-label promotion of Lexapro for use in children; hid the results of a study showing lack of effectiveness in children; paid kickbacks to physicians to induce them to prescribe Lexapro to children; and conducted so-called “seeding studies” that were, in reality, marketing efforts to promote the drug’s use by doctors. Forest denied the allegations but ultimately agreed to settle with the plaintiffs for over $313 million.

Brand Names

Escitalopram is sold under many brand names worldwide such as Cipralex, Lexapro, Mozarin, Aciprex, Depralin, Ecytara, Elicea, Nexpram, Pramatis, and Betesda.

What is Fluvoxamine?

Introduction

Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class which is used primarily for the treatment of depression disorder and obsessive-compulsive disorder (OCD). It is also used to treat anxiety disorders, such as panic disorder, social anxiety disorder, and post-traumatic stress disorder.

Fluvoxamine’s side-effect profile is very similar to other SSRIs: constipation, gastrointestinal problems, headache, anxiety, irritation, sexual problems, dry mouth, sleep problems and a risk of suicide at the start of treatment by lifting the psychomotor inhibition, but these effects appear to be significantly weaker than with other SSRIs (except gastrointestinal side-effects). The tolerance profile also appears to be quite superior than other SSRIs, despite its age.

Anti-inflammatory effects of fluvoxamine are being researched to determine if it can be used to treat COVID-19. It is not approved by the US Federal Drug Administration (FDA) for treatment of any infection.

Brief History

Fluvoxamine was developed by Kali-Duphar, part of Solvay Pharmaceuticals, Belgium, now Abbott Laboratories, and introduced as Floxyfral in Switzerland in 1983. It was approved by the FDA in 1994, and introduced as Luvox in the US. In India, it is available, among several other brands, as Uvox by Abbott. It was one of the first SSRI antidepressants to be launched, and is prescribed in many countries to patients with major depression. It was the first SSRI, a non-TCA drug, approved by the FDA specifically for the treatment of OCD. At the end of 1995, more than ten million patients worldwide had been treated with fluvoxamine. Fluvoxamine was the first SSRI to be registered for the treatment of obsessive compulsive disorder in children by the FDA in 1997. In Japan, fluvoxamine was the first SSRI to be approved for the treatment of depression in 1999 and was later in 2005 the first drug to be approved for the treatment of social anxiety disorder. Fluvoxamine was the first SSRI approved for clinical use in the United Kingdom.

Medical Uses

In many countries (e.g. Australia, the UK, and Russia) it is commonly used for major depressive disorder. Fluvoxamine is also approved in the United States for OCD, and social anxiety disorder. In Japan it is also approved to treat OCD, social anxiety disorder (SAD) and major depressive disorder (MDD). Fluvoxamine is indicated for children and adolescents with OCD. The drug works long-term, and retains its therapeutic efficacy for at least one year. It has also been found to possess some analgesic properties in line with other SSRIs and tricyclic antidepressants.

There is tentative evidence that fluvoxamine is effective for social phobia in adults. Fluvoxamine is also effective for generalised anxiety disorder (GAD), SAD, panic disorder and separation anxiety disorder in children and adolescents. There is tentative evidence that fluvoxamine may help some people with negative symptoms of chronic schizophrenia.

Adverse Effects

Gastrointestinal side effects are more common in those receiving fluvoxamine than with other SSRIs. Otherwise, fluvoxamine’s side-effect profile is very similar to other SSRIs.

Common (1-10% Incidence) Adverse Effects

  • Nausea.
  • Vomiting.
  • Weight loss.
  • Yawning.
  • Loss of appetite.
  • Agitation.
  • Nervousness.
  • Anxiety.
  • Insomnia.
  • Somnolence (drowsiness).
  • Tremor.
  • Restlessness.
  • Headache.
  • Dizziness.
  • Palpitations.
  • Tachycardia (high heart rate).
  • Abdominal pain.
  • Dyspepsia (indigestion).
  • Diarrhoea.
  • Constipation.
  • Hyperhidrosis (excess sweating).
  • Asthenia (weakness).
  • Malaise.
  • Sexual dysfunction (including delayed ejaculation, erectile dysfunction, decreased libido, etc.).
  • Xerostomia (dry mouth).

Uncommon (0.1-1% Incidence) Adverse Effects

  • Arthralgia.
  • Hallucination.
  • Confusional state.
  • Extrapyramidal side effects (e.g. dystonia, parkinsonism, tremor, etc.).
  • Orthostatic hypotension.
  • Cutaneous hypersensitivity reactions (e.g. oedema [buildup of fluid in the tissues], rash, pruritus).

Rare (0.01-0.1% Incidence) Adverse Effects

  • Mania.
  • Seizures.
  • Abnormal hepatic (liver) function.
  • Photosensitivity (being abnormally sensitive to light).
  • Galactorrhoea (expulsion of breast milk unrelated to pregnancy or breastfeeding).

Unknown Frequency Adverse Effects

  • Hyperprolactinaemia (elevated plasma prolactin levels leading to galactorrhoea, amenorrhoea [cessation of menstrual cycles], etc.).
  • Bone fractures.
  • Glaucoma.
  • Mydriasis.
  • Urinary incontinence.
  • Urinary retention.
  • Bed-wetting.
  • Serotonin syndrome: A potentially fatal condition characterised by abrupt onset muscle rigidity, hyperthermia (elevated body temperature), rhabdomyolysis, mental status changes (e.g. coma, hallucinations, agitation), etc.
  • Neuroleptic malignant syndrome – practically identical presentation to serotonin syndrome except with a more prolonged onset.
  • Akathisia – a sense of inner restlessness that presents itself with the inability to stay still.
  • Paraesthesia.
  • Dysgeusia.
  • Haemorrhage.
  • Withdrawal symptoms.
  • Weight changes.
  • Suicidal ideation and behaviour.
  • Violence towards others.
  • Hyponatraemia.
  • Syndrome of inappropriate antidiuretic hormone secretion.
  • Ecchymoses.

Interactions

Fluvoxamine inhibits the following cytochrome P450 enzymes:

  • CYP1A2 (strongly) which metabolises agomelatine, amitriptyline, caffeine, clomipramine, clozapine, duloxetine, haloperidol, imipramine, phenacetin, tacrine, tamoxifen, theophylline, olanzapine, etc.
  • CYP3A4 (moderately) which metabolises alprazolam, aripiprazole, clozapine, haloperidol, quetiapine, pimozide, ziprasidone, etc.
  • CYP2D6 (weakly) which metabolises aripiprazole, chlorpromazine, clozapine, codeine, fluoxetine, haloperidol, olanzapine, oxycodone, paroxetine, perphenazine, pethidine, risperidone, sertraline, thioridazine, zuclopenthixol, etc.[43]
  • CYP2C9 (moderately) which metabolises nonsteroidal anti-inflammatory drugs, phenytoin, sulfonylureas, etc.
  • CYP2C19 (strongly) which metabolises clonazepam, diazepam, phenytoin, etc.
  • CYP2B6 (weakly) which metabolises bupropion, cyclophosphamide, sertraline, tamoxifen, valproate, etc.

By so doing, fluvoxamine can increase serum concentration of the substrates of these enzymes.

The plasma levels of oxidatively metabolised benzodiazepines (e.g. triazolam, midazolam, alprazolam and diazepam) are likely to be increased when co-administered with fluvoxamine. However the clearance of benzodiazepines metabolised by glucuronidation (e.g. lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine. It appears that benzodiazepines metabolised by nitro-reduction (clonazepam, nitrazepam) are unlikely to be affected by fluvoxamine. Using fluvoxamine and alprazolam together can increase alprazolam plasma concentrations. If alprazolam is co-administered with fluvoxamine, the initial alprazolam dose should be reduced to the lowest effective dose.

Fluvoxamine and ramelteon co-administration is not indicated.

Fluvoxamine has been observed to increase serum concentrations of mirtazapine, which is mainly metabolised by CYP1A2, CYP2D6, and CYP3A4, by three- to four-fold in humans. Caution and adjustment of dosage as necessary are warranted when combining fluvoxamine and mirtazapine.

Fluvoxamine seriously affects the pharmacokinetics of tizanidine and increases the intensity and duration of its effects. Because of the potentially hazardous consequences, the concomitant use of tizanidine with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided.

Fluvoxamine’s interaction with St John’s wort can lead to increased serotonin levels and potentially lead to serotonin syndrome.

Pharmacology

Fluvoxamine is a potent selective serotonin reuptake inhibitor with around 100-fold affinity for the serotonin transporter over the norepinephrine transporter. It has negligible affinity for the dopamine transporter or any other site, with the sole exception of the σ1 receptor. It behaves as a potent agonist at this receptor and has the highest affinity (36 nM) of any SSRI for doing so. This may contribute to its antidepressant and anxiolytic effects and may also afford it some efficacy in treating the cognitive symptoms of depression. Unlike some other SSRI, fluvoxamine’s metabolites are pharmacologically neutral.

Society and Culture

Manufacturers include BayPharma, Synthon, and Teva, among others. Luvox was notably used by Eric Harris, one of the Columbine shooters.

Book: The End of Mental Illness

Book Title:

The End of Mental Illness: How Neuroscience Is Transforming Psychiatry and Helping Prevent or Reverse Mood and Anxiety Disorders, ADHD, Addictions, PTSD, Psychosis, Personality Disorders, and More.

Author(s): Daniel G. Amen.

Year: 2020.

Edition: First (1st).

Publisher: Tyndale House Publishers.

Type(s): Hardcover, Paperback, Audiobook, and Kindle.

Synopsis:

Though incidence of these conditions is skyrocketing, for the past four decades standard treatment has not much changed, and success rates in treating them have barely improved, either. Meanwhile, the stigma of the “mental illness” label – damaging and devastating on its own – can often prevent sufferers from getting the help they need.

Brain specialist and bestselling author Dr. Daniel Amen is on the forefront of a new movement within medicine and related disciplines that aims to change all that. In The End of Mental Illness, Dr. Amen draws on the latest findings of neuroscience to challenge an outdated psychiatric paradigm and help readers take control and improve the health of their own brain, minimising or reversing conditions that may be preventing them from living a full and emotionally healthy life.

The End of Mental Illness will help you discover:

  • Why labelling someone as having a “mental illness” is not only inaccurate but harmful.
  • Why standard treatment may not have helped you or a loved one – and why diagnosing and treating you based on your symptoms alone so often misses the true cause of those symptoms and results in poor outcomes.
  • At least 100 simple things you can do yourself to heal your brain and prevent or reverse the problems that are making you feel sad, mad, or bad.
  • How to identify your “brain type” and what you can do to optimise your particular type.
  • Where to find the kind of health provider who understands and uses the new paradigm of brain health.